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CN1046281C - Pharmacologically active enantiomers and methods for their preparation - Google Patents

Pharmacologically active enantiomers and methods for their preparation Download PDF

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CN1046281C
CN1046281C CN94193226A CN94193226A CN1046281C CN 1046281 C CN1046281 C CN 1046281C CN 94193226 A CN94193226 A CN 94193226A CN 94193226 A CN94193226 A CN 94193226A CN 1046281 C CN1046281 C CN 1046281C
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physiologically acceptable
alk
acceptable acid
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CN1129939A (en
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L·拜奥奇
V·西奥里
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Angelini Ricerche SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

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Abstract

The (S) or (R) enantiomer of a compound of formula: wherein ALK is an alkyl group having 1 to 3 carbon atoms.

Description

Enantiomorph of pharmacologically active and preparation method thereof
The present invention relates to the enantiomorph of pharmacologically active, can accept the salt of acid on its physiology, the pharmaceutical composition for preparing their method and contain them.
PCT/EP93/00080 discloses the new compound of the following general formula of a class: I is R only wherein, R, R " and one of R for the alkyl that contains 1-3 carbon atom other be hydrogen.
The data presentation formula I compound of the pharmacology of reporting in above-mentioned application has the triazolone of being similar to (I, the R=R '=R " pharmacological properties of=R =H), but also have some advantage, as reduced the avidity to adrenergic receptor.
We (S) that be surprised to find formula I compound (R wherein, R ', R are hydrogen and R " be the alkyl that contains 1-3 carbon atom) compares the analgesic activity with improvement with (R) enantiomorph with their racemic modification now.
This discovery more allow the people surprised be to compare two kinds of enantiomorphs all to have lower anti-alpha-adrenergic activity with corresponding racemic modification, and then reduced side effect.
Therefore, first purpose of the present invention provide (S) of following formula: compound and (R) enantiomorph and with physiology on can accept acid with the salt formula: (I A) wherein Alk is the alkyl that contains 1-3 carbon atom,
The example of suitable acid is a hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, lactic acid, succsinic acid, acetate, tartrate, oxysuccinic acid, citric acid, phenylformic acid, 2-naphthene sulfonic acid, hexanodioic acid and pimelic acid.
Although (R) and (S) enantiomorph is all active big than corresponding racemic modification,, (S) enantiomorph is also bigger than the activity of (R) enantiomorph.Therefore, (S) enantiomorph is preferred.
With regard to Alk, methyl is preferred.
Therefore, preferred compound of the present invention is that wherein Alk is (S) enantiomorph of formula (1A) of methyl.
The analgesic activity of The compounds of this invention passes through subcutaneous administration (Pharmacol.Exp.Ther., 125, pp237-240,1959) with the test of phenyl quinone on one's body mouse and obtains proof.Handle 30 animals with each product.Test-results is listed in table 1.
Table 1
Chemical compounds I A Analgesic activity phenyl quinone, ED 50(mg/kg)
Form Alk
Racemic modification (R) (S) CH 3 CH 3 CH 3 ＞12.50 9.02 7.80
Table 1 explanation will obtain identical analgesic effect, and racemic compound is needed higher dosage.This just means that racemic compound is lower than the analgesic activity of single enantiomorph.Table 1 also illustrates the active height of (S) enantiomorph than (R) enantiomorph.
Because the interference to adrenergic system is a sign of side effect, so measured the ability of two kinds of enantiomorphs in conjunction with the alpha-1 adrenergic acceptor, i.e. IC 50The anti-alpha-adrenergic activity (table 3) of (table 2) and same compound.
With regard to receptor binding assays, with reference to " Molecular Pharmacology ", 20,295-301, (1981).
Moreover, according to " Clinical and Experimental Pharmacology ﹠amp; Physiology " 6,275-279, technology described in (1979) has been measured anti-alpha-adrenergic activity on isolated organ (vas deferens of rat).
Test-results is listed in table 2 and table 3.
Table 2
Chemical compounds I L Avidity (IC to the alpha-1 adrenergic acceptor 50)
Form Alk
Racemic modification (R) (S) CH 3 CH 3 CH 3 471 533 981
Table 3
Chemical compounds I A The active pA of anti-alpha-adrenergic 2
Form Alk
Racemic modification (R) (S) CH 3 CH 3 CH 3 7.70±0.7 6.75±0.2 5.40±0.7
In table 2, be that the IC50 value is low to alpha-1 adrenergic receptor affinity height, and in table 3, the active height of anti-alpha-adrenergic is that the PA2 value is high.Therefore, the data of table 2 and table 3 also are fully unexpected, because having shown simultaneously, they disturb adrenergic receptor and anti-alpha-adrenergic activity, thereby (S) and (R) side effect of enantiomorph is littler than its racemic modification, and (S) anti-alpha-adrenergic specific activity (R) enantiomorph of enantiomorph is low.
Therefore, concerning formula (I A) enantiomorph and racemic modification, analgesic activity is high more, and unwanted anti-alpha-adrenergic activity is low more.
The compounds of this invention can be by making its optical activity acid salt classification crystallization and be prepared by stereospecific synthesis.
Verified in first method, tartaric salt is useful especially.
Therefore, second purpose of the present invention provides the method for a kind of preparation formula (I A) enantiomorph, it is characterized in that with (R, R or S, S) tartrate is the salinization of racemic formula (I A) compound, two kinds of diastereomeric salts of gained are separated from The suitable solvent with fractionation crystallization, and, if desired, with gained enantiomorph and physiologically acceptable sour salify.
The example of suitable solvent is rudimentary alcohol and water.
Enantiomorph of the present invention is with (S) salt of tartrate formation also is new thereby has constituted the 3rd purpose of the present invention for R, R or S.
Another object of the present invention provides the stereospecific synthesis method of formula (I A) enantiomorph and physiologically acceptable acid salt thereof, it is characterized in that formula III compound or its an alkali metal salt:
Figure C9419322600091
(III)
With the formula II diethylenediamine compound:
Figure C9419322600101
(II) wherein Alk as above defines, and X is for being selected from chlorine, bromine and-O-SO 2The leaving group of-Z (wherein Z is an alkyl or aryl) because of, and compound (II) has definitely (R) or (S) configuration, in the presence of the mixture of suitable organic thinner or organic thinner, to between the boiling temperature of reaction mixture, react between 40 ℃ in temperature, and, if desired, with gained enantiomorph and physiologically acceptable sour salify.
Above-mentioned reaction mainly is that secondary amino group is alkalized, so it can be according to routine techniques (J.March, Advanced Organic Chemistry, 3rd ed, J.Wiley﹠amp; Sons, N.Y.Pages 364-365) carry out.
Preferably, the formula III compound is with the salt of alkali US-A-3 for example, the sodium-salt form reaction described in 381,009.
The typical definition of Z is a methyl, phenyl, tolyl and right-bromo-phenyl.
The preferred sodium salt by the formula III compound of this reaction and formula II compound are in the presence of the mixture of suitable organic thinner or organic thinner, and temperature in office is carried out to reacting between the boiling temperature of reaction mixture between 40 ℃.The example of suitable organic thinner is an aromatic hydrocarbon, Fatty Alcohol(C12-C14 and C12-C18), acid amides and composition thereof.
The example of preferred aromatic hydrocarbon is benzene, toluene and dimethylbenzene.The example of Fatty Alcohol(C12-C14 and C12-C18) is butanols, the trimethyl carbinol, sec-butyl alcohol, isopropylcarbinol, amylalcohol and tertiary amyl alcohol.The representative instance of preferred amide is a dimethylformamide.
Moreover, or the stereospecific synthesis of (II) compound can followingly carry out formula (VIII) compound (VIII) wherein Alk as above defines, and X is CH 3-O-SO 2-O-or halogen, reaching Y is the alkyl that contains the 1-3 carbon atom, formula (VIII) has definitely (S) or (R) configuration, reacts with formula (VII) compound
Figure C9419322600112
(VII) produces the formula VI compound (VI) wherein Y and Alk as above defines, and when the compound VIII had (S) configuration, compound had (R) exhausted structure-type, and vice versa.
Compound (VIII) and compound (VII) reaction produce compound (VI) and preferably carry out in the presence of acid acceptor and suitable solvent.
The example of suitable acid acceptor is triethylamine and pyridine.
The example of suitable solvent is aromatic hydrocarbon such as toluene and dimethylbenzene.
Formula (V) compound that then compound (VI) cyclisation generation and compound (VI) is had identical absolute configuration. (Ⅴ)
With compound (VI) cyclisation is that the synthetic technology that compound (V) can not be used in the described relevant corresponding racemic compound of PCT/EP93/00080 is carried out, because described technology causes complete racemization.After the many unsuccessful trial of the recovery of having carried out causing racemization or unreacted compound (VI), be surprised to find that required cyclisation is easy to carry out, be about to compound (VI) and be dissolved in the aqueous solution of strong acid, and separate required compound (V) by alkalization gained solution through simple heating back.
This example of typical case of preferred strong acid is a hydrochloric acid.
Then gained compound (V) is reduced with the method for reaction process 3 described in similar above-mentioned patent application PCT/EP93/00080.
Then this preparation is carried out with the mode of relevant reaction process 2 described in the similar above-mentioned patent application.
In cyclisation step (VI → V) and all subsequent steps, all do not have configuration conversion, so the final formula of gained (I A) compound has identical absolute configuration with compound (V).Even possible racemization also is few.
For practical application, directly administration but of The compounds of this invention preferably with the form administration of pharmaceutical composition.
These compositions are the additive salt that can accept acid on the enantiomorph of another object of the present invention and said composition (the I A) that contain at least a therapeutic dose or its physiology, and the liquid or solid pharmaceutical carrier.
Pharmaceutical composition of the present invention can be solid such as tablet, drageeing, and capsule, pulvis and control-released agent, or semiliquid, as emulsifiable paste and ointment, or liquid, as solution, suspension and emulsion.
Except conventional carrier, the present composition can contain other appropriate drug additive, as sanitas, and stablizer, emulsifying agent, salt, buffer reagent, tinting material and the seasonings of adjusting osmotic pressure.
If in order to treat needs, be other useful compatibility effective constituent to treatment when the present composition can also contain administration simultaneously.
For therapeutic purpose, the significant quantity of desiring formula (I A) enantiomorph of administration can need according to all multifactor as concrete treatments, pharmaceutical composition, the validity of medication and the concrete enantiomorph of used the present invention and changing in wide range.Yet, can select best significant quantity with simple ordinary method.
In general, dosage preferable range every day of formula (I A) enantiomorph is 0.1～10mg/g.
Pharmaceutical composition of the present invention can be prepared according to known routine techniques in the pharmaceutical chemistry, and these technology comprise mixing, granulating and extruding, and if desired, violent mixing and solvent components then can obtain to be fit to the product innovation of needs.
The following example is used for illustrating the present invention.
Embodiment 1
With 12.5g (0.032moles) racemic modification (I, R=R '=R =H; R "=CH 3) naturally occurring (R, R) mixture of tartaric 125ml absolute ethanol is being heated to dissolving fully near of short duration under the boiling temperature for (as alkali) and 4.8g (0.032moles).
The solid of refrigerated separation collected with filtration method and from absolute ethanol recrystallization up to obtaining the constant fusing point.
M.p.151-152 ℃, [α] D 20=+13.2 ± 0.3 (1% the aqueous solution).
By salt suspension is also under agitation used the corresponding alkali of powder carbonic acid potash acquisition in water.
Resistates fusing point with dichloromethane extraction is 63-65 ℃ (hexane), [α] D 20=+32.0 ± 0.3 (1% absolute ethanol solution).
Hydrochloride, m.p.122-124 ℃ (from ethanol, moisture absorption);
Vitriol, m.p.204-205 ℃;
Maleate, m.p.142-143 ℃.
From filtrate, reclaim (R) alkali, [(S), (R, R) salt is separated in front], and be dissolved in the absolute ethanol.
With equimolar amount (S, S) tartrate is added in this solution.Through refrigerated separation (R) (S, S) salt.This salt is with (S) (R, R) salt has identical fusing point (151-152 ℃), [α] D 20=-13.2 ± 0.3.
The fusing point of corresponding alkali is 63-65 ℃; [α] D 20=-32.0 ± 0.3 (1% alcoholic acid solution).
Hydrochloride, m.p.122-124 ℃ (moisture absorption).
Embodiment 2
A) (R)-1-(3-chloro-phenyl-)-3-methyl-piperazine-2-ketone (formula V, Alk=CH 3)
With 18.4g (0.108moles) N-(3-chloro-phenyl-) quadrol (J.Med.Chem., G, 858-860 (1966), 19.3ml (0.119moles) (S)-the 200ml toluene solution of methylsulfonyl-ethyl lactate and 22.8ml (0.163moles) triethylamine boils and refluxes and spend the night.
Reaction mixture is washed with water and extract with the 1N hydrochloric acid soln.With powder carbonic acid potash water and use dichloromethane extraction.With flash chromatography (silica gel, hexane-ethyl acetate 1: 1) purifying gained alkali
Gained oily resistates behind the evaporating solvent is dissolved in 10 parts of (weight) 2N hydrochloric acid and gained solution is boiled up to starting raw material disappear (TLC).
By separating required product [α] with alkaline carbonate (sodium or potassium) alkalization D 20=+50.0.
B) (R)-and 2-[3-[4-(3-chloro-phenyl-)-1-(2-methyl)-piperazinyl] propyl group]-1,2,4-triazolo [4,3-a]-pyridine-3 (2H)-ketone (formula I A, Alk=CH 3)
With method described in similar patent application PCT/EP93/00080, the compound starting raw material for preparing with preceding step (a) prepares title compound.
Alkali, [α] D 20=-31.8 (1% ethanolic solns).
Hydrochloride, m.p.122-124 ℃ (also with the sample mix for preparing according to embodiment 1).
(R)-1-(3-chloro-phenyl-)-3-methylpiperazine intermediate (formula IV, Alk=CH 3) have a specific rotation [α] D 20=+15.0 (1% ethanolic solns).
Embodiment 3
(S)-2-[3-[4-(3-chloro-phenyl-)-1-(2-methyl)-piperazinyl]-propyl group]-1,2,4-triazolo [4,3-a]-pyridine-3 (2H)-ketone (formula I A, Alk=CH 3)
Prepare title compound with similar embodiment 2 described methods, just (the R)-2-bromo-ethyl propionate with equimolar amount replaces (S)-methylsulfonyl-ethyl lactate.
Alkali, m.p.63-65 ℃, [α] D 20=+32.0 ± 0.3 (1% ethanolic soln).

Claims (13)

1．下式化合物的(S)或(R)对映体及其生理上可接受的酸加成盐：
Figure C9419322600021
(ⅠA)其中Alk为含有1-3个碳原子的烷基。1. (S) or (R) enantiomers of compounds of the following formula and their physiologically acceptable acid addition salts:
Figure C9419322600021
(IA) wherein Alk is an alkyl group having 1 to 3 carbon atoms. 2．根据权利要求1的化合物，该化合物是(R)-2-〔3-〔4-(3-氯苯基)-1-(2-甲基)哌嗪基〕-丙基〕-1,2,4-三唑并〔4,3-a〕-吡啶-3(2H)-酮及其生理上可接受的酸加成盐。2. The compound according to claim 1, which is (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)piperazinyl]-propyl]-1,2 , 4-Triazolo[4,3-a]-pyridin-3(2H)-one and its physiologically acceptable acid addition salts. 3．根据权利要求1的化合物，该化合物是(S)-2-〔3-〔4-(3-氯苯基)-2-(2-甲基)-哌嗪基〕-丙基〕-1,2,4-三唑并〔4,3-a〕-吡啶-3(2H)-酮及其生理上可接受的酸加成盐。3. A compound according to claim 1, which is (S)-2-[3-[4-(3-chlorophenyl)-2-(2-methyl)-piperazinyl]-propyl]-1, 2,4-Triazolo[4,3-a]-pyridin-3(2H)-one and its physiologically acceptable acid addition salts. 4．根据权利要求1的化合物，该化合物是(R)-2-〔3-〔4-(3-氯苯基)-1-(2-甲基)-哌嗪基〕-丙基〕-1,2,4-三唑并〔4,3-a〕-吡啶-3(2H)-酮(S,S)酒石酸盐。4. A compound according to claim 1, which is (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]-1, 2,4-Triazolo[4,3-a]-pyridin-3(2H)-one (S,S) tartrate. 5．根据权利要求1的化合物，该化合物是(S)-2-〔3-〔4-(3-氯苯基)-1-(2-甲基-哌嗪基〕-丙基〕-1,2,4-三唑并〔4,3-a)-吡啶-3(2H)-酮(R,R)酒石酸盐。5. The compound according to claim 1, which is (S)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl-piperazinyl]-propyl]-1,2 , 4-Triazolo[4,3-a)-pyridin-3(2H)-one (R,R) tartrate. 6．一种制备式(ⅠA)对映体或其生理上可接受的酸加成盐的方法(ⅠA)其中Alk为含有1-3个碳原子的烷基，其特征在于6. A kind of method for preparing formula (IA) enantiomer or its physiologically acceptable acid addition salt (IA) where Alk is an alkyl group containing 1-3 carbon atoms, characterized in that (a)用(R,R或S,S)酒石酸盐化式(ⅠA)的外消旋混合物，(b)用分级结晶法从适宜溶剂中分离所得两种非对映体盐，及如果需要，(a) tartrate the racemic mixture of formula (IA) with (R, R or S, S), (b) separate the resulting two diastereomeric salts from a suitable solvent by fractional crystallization, and if desired , (c)用生理上可接受的酸盐化所得对映体。(c) Saltifying the resulting enantiomer with a physiologically acceptable salt. 7．根据权利要求6的方法，其特征在于在步骤(b)中所用溶剂为低级醇或水。7. The method according to claim 6, characterized in that the solvent used in step (b) is lower alcohol or water. 8．一种制备式(ⅠA)对映体或其生理上可接受的酸加成盐的方法
Figure C9419322600032
(ⅠA)其中Alk为含有1-3个碳原子的烷基，8. A kind of method for preparing formula (IA) enantiomer or its physiologically acceptable acid addition salt
Figure C9419322600032
(IA) wherein Alk is an alkyl group containing 1-3 carbon atoms, 其特征在于It is characterized by (a)式Ⅲ化合物或其碱金属盐
Figure C9419322600041
(Ⅲ)(a) Formula III compound or its alkali metal salt
Figure C9419322600041
(Ⅲ) 与式(Ⅱ)的哌嗪化合物(Ⅱ)With the piperazine compound of formula (II) (Ⅱ) 其中Alk如上述定义，及where Alk is as defined above, and X″为选自氯，溴和-O-SO3-Z的离去基团，其中Z为烷基或芳基，并且化合物(Ⅱ)具有绝对(R)或(S)构型在适宜的有机稀释剂或有机稀释剂的混合物存在下及在温度介于40℃至反应混合物的沸点间反应，并且，如果需要，用生理上可接受的酸盐化所得对映体。X" is a leaving group selected from chlorine, bromine and -O-SO 3 -Z, wherein Z is an alkyl or aryl group, and compound (II) has an absolute (R) or (S) configuration where appropriate The reaction is carried out in the presence of an organic diluent or a mixture of organic diluents at a temperature between 40° C. and the boiling point of the reaction mixture and, if desired, the resulting enantiomer is acidified with a physiologically acceptable acid salt. 9．根据权利要求8的方法，其特征在于Z为甲基，苯基，甲苯基和对-溴-苯基。9. Process according to claim 8, characterized in that Z is methyl, phenyl, tolyl and p-bromo-phenyl. 10．根据权利要求8或9的方法，其特征在于适宜有机稀释剂为芳香烃，脂肪醇或酰胺。10. Process according to claim 8 or 9, characterized in that suitable organic diluents are aromatic hydrocarbons, fatty alcohols or amides. 11．根据权利要求10的方法，其特征在于芳香烃为苯，甲苯或二甲苯。11. Process according to claim 10, characterized in that the aromatic hydrocarbon is benzene, toluene or xylene. 12．根据权利要求11的方法，其特征在于脂肪醇为丁醇，叔丁醇，仲丁醇，异丁醇，戊醇和叔戊醇。12. Process according to claim 11, characterized in that the fatty alcohol is butanol, tert-butanol, sec-butanol, isobutanol, amyl alcohol and tert-amyl alcohol. 13．根据权利要求10的方法，其特征在于酰胺为二甲基酰胺。13. Process according to claim 10, characterized in that the amide is dimethylamide.
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RU2706700C1 (en) 2019-09-24 2019-11-20 Общество с ограниченной ответственностью "Научно-производственная компания "СКиФФ" Pharmaceutical composition for correcting behavior of cats and dogs in stress situations
US20230391771A1 (en) * 2020-10-07 2023-12-07 Amgen Inc. Process for racemizing and isolating atropisomers of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1h,3h)-dione

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